WO2013084150A1 - Novel crystal form of (2s)-2-amino-3-hydroxy-n-[2-methoxy-2-[(1z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide and method of preparation thereof - Google Patents
Novel crystal form of (2s)-2-amino-3-hydroxy-n-[2-methoxy-2-[(1z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide and method of preparation thereof Download PDFInfo
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- WO2013084150A1 WO2013084150A1 PCT/IB2012/056953 IB2012056953W WO2013084150A1 WO 2013084150 A1 WO2013084150 A1 WO 2013084150A1 IB 2012056953 W IB2012056953 W IB 2012056953W WO 2013084150 A1 WO2013084150 A1 WO 2013084150A1
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- compound
- formula
- phenyl
- methoxy
- propanamide
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- 0 COc1cc(C(*)=C[C@@](CC=C2OC)C=C2N*)cc(I)c1OC Chemical compound COc1cc(C(*)=C[C@@](CC=C2OC)C=C2N*)cc(I)c1OC 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a novel crystal form, hereinafter referred to as crystal Form ⁇ , of (2S)-2-amino-3-hydroxy-N-[2-memoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl] phenyl]propanamide .
- the invention also relates to processes for the preparation of said crystal Form I. pharmaceutical compositions and medicament comprising it, and its therapeutic use more particularly in the prevention and/or treatment, of cancers and/or tumors.
- Cancer is a disease of humans and animals which is for the most part fatal and which is caused by the uncontrolled growth of endogenous cells. Cancer is the term for the formation of malignant tumors (malignomas) and of neoplasm (tumors or carcinomas) or for the malignant degeneration and disturbed maturation of white blood cells (leukemia, blood cancer).
- the present invention relates more particularly to the anti-cancer compound named (2S)-2-ammo-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl] phenyl] propanamide or (Z)-N-[2-memoxy-5-[2-(3,4,5 rimethoxyphenyl)vinyl]phenyl]--L-serinamide, a well known combretastatin derivative known under the INN (International Non-proprietary Name) ombrabulin, which has the following structure of formula (A):
- VDA vascular disrupting agent
- R 1 , R 2 , R 3 and R 4 each independently represents a C 1 -3 alkyl group.
- the present invention concerns the obtention of a new crystal form of ombrabulin, as its free base form.
- crystal polymorphism is due to the ability of a compound to change its molecular conformation or to form different inter- and or intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom aiTangements in the crystal lattice of different polymorphs.
- polymorphs of a compound can differ notably from each other by different energies in their crystal lattices and, therefore, generally have specific physical properties in the solid state such as crystal morphology, density, melting point, colour, chemical and physical stability, hygroscopy, solubility, dissolution rate, granular properties...
- polymorphic forms of the same compound can exhibit different behaviors in terms of formulation, therapeutic activity and chemical and physical stability.
- crystal Form I the compound of formula (A), as its free base form, can exist in a crystal form which is hereinafter referred to as crystal Form I.
- the present invention provides a novel crystal form of (2S)-2-amino-3-hydroxy- N-[2-methoxy ⁇ 2-[(l Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide of formula (A)
- crystal Form I of compound of formula (A) has at least one of the following characteristics:
- Another aspects of the present invention are processes for the preparation of said crystal Form I of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5- trimethoxyphenyl)ethenyl]phenyl] propanamide.
- the present invention is directed to a particular process for preparing crystal Form I of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5- trimethoxyphenyl)ethenyl]phenyl]propanamide comprising at least the step a) consisting to put in contact the hydrochloride salt of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5- trimethoxyphenyl)ethenyl] phenyl]propanamide of formula (B):
- Said compound of formula (B) can be prepared by conventional methods of organic synthesis practiced by those skilled in the art.
- step a) is advantageously sodium hydroxide.
- condition appropriate to promote the crystallization it is meant that the process according to the invention comprises:
- step c By “partially distilling” in step c), it is meant a distillation of the isopropyl acetate so as to remove a part of the solvent (i.e. the removal of the solvent is not complete).
- the distillation removes at least 20% of said solvent, more advantageously at least half of the solvent.
- the step d) of cooling the medium below room temperature is advantageously carried out down to a temperature of about 5°C, advantageously down to 5°C ⁇ 5°C.
- the step d) of cooling the medium below room temperature is advantageously followed by a step e) of maintaining the medium at the temperature achieved in the preceding step, for a duration of at least about 1 hour, advantageously for 1 to 2 hours.
- the step d) of cooling the medium below room temperature may be preceded by a step d') of cooling the medium at about room temperature, advantageously at about 20°C, such as 20°C ⁇ 5°C.
- the reaction medium is advantageously maintained at such a temperature for a few to several hours, such as about 12 hours.
- the process according to the instant invention advantageously comprises a final step f) comprising the filtration, washing and drying of the crystal Form I of (2S)-2-amino-3-hydroxy-N-i2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] propanamide obtained as a result of the preceding steps.
- the washing is advantageously earned out with isopropyl acetate.
- a first variant consists in preparing and isolating the hydrochloride form of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] propanamide (compound (B)), and then carrying out the above-defined crystallization steps so as to obtain the compound (A), Form I;
- a second variant is carried out without the prior isolation of the hydrochloride form of compound (A) (compound (B)), and consists in carrying out in situ the crystallization steps defined above, on a non-isolated intermediate (compound (B)) obtained starting from intermediate (Z)-(Ib) as defined below.
- the process for preparing crystal Form I of (2S)'2-amino-3 ⁇ hydroxy-rl-[2-memoxy-2-[(lZ)-2-(3,4,5-trim.ethoxyphenyl)ethenyl]phenyl] propanamide may therefore comprise the preliminary step of synthesizing the hydrochloride salt of (2S)-2-ammo-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl] phenyl]propanamide, the crystallization step a) being carried out in situ by using a solvent like isopropyl acetate and applying the above defined steps to the so obtained hydrochloride derivative.
- the processes according to the instant invention are particularly advantageous over the processes of preparation of ombrabulin base disclosed in the prior art since they do not comprise any purification steps by chromatography in order to recover the crystals of the compound of formula (A), and since they provide said compound of formula (A) Form I in good yields and with excellent chemical purity (higher than or equal to 99.5%).
- the invention provides crystal Form 1 of (2S)-2-amino-3- hydroxy-N-[2-methoxy-2-[( lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] propanamide as defined herein substantially free of any other polymorph(s).
- the ciystal Form I comprises less than 10%, preferably less than 2%, more preferably less than 0.5%, of any other polymorph(s) or impurity or impurities .
- said crystal Form I of compound of formula (A) has an X-ray powder diffraction diagram substantially identical to that of Figure 1.
- said crystal Form I of compound of formula (A) has an X-ray powder diffraction diagram substantially identical to that of Figure 1.
- (A) has thermo-gravimetric analysis data substantially identical to that of Figure 2 in which no weight loss is observed from room temperature up to 170°C (i.e. up to a temperature far beyond 104°C which is the compound melting temperature).
- said crystal Form I is an anhydrous compound.
- said crystal Form I of compound of formula (A) has a water sorption/desorption 25°C isotherm substantially identical to that of Figure 3 in which no significant water uptake is observed. Said crystal form is thus not hygroscopic. Said crystal Form I is a stable anhydrous and non-hygroscopic crystal solid form. These characteristics are particularly advantageous for the processes of formulation, for the stability of said compound and thus for the conditions of storage.
- said compound of formula (A) Form I according to the invention is useful for obtaining different addition salts of said compound with a pharmaceutically acceptable acid, for example the hydrochloride salt.
- a pharmaceutically acceptable acid for example the hydrochloride salt.
- Said compound of formula (A) Form I can advantageously be used directly to prepare formulation, by extemporaneous formation of an addition salt of said compound with a pharmaceutically acceptable acid,, for example hydrochloride salt, by addition of the corresponding acid, for example hydrochloric acid.
- a pharmaceutically acceptable acid for example hydrochloride salt
- the present invention also relates to said crystal Form I of (2S)-2-amino-3- hydroxy-N-[2 ⁇ methoxy ⁇ 2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyi]phenyl]propanamide as a medicament.
- the present invention provides, said crystal Form I of (2S)- 2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl] phenyl] propanamide for its use for preventing and/or treating cancers and/or tumors.
- Another aspect of the present invention is the use of said crystal Form I of (2S)-2-amino-3-hydi xy-N-[2-methoxy-2-[(lZ)-2-(3,4,5-tnmethoxyphenyl)ethenyl] phenyl] propanamide for preventing and/or treating cancers and/or tumors.
- Another aspect of the present invention is the use of said crystal Form I of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl] phenyl] propanamide for the manufacture of a medicament useful for preventing and/or treating cancers and/or tumors.
- crystal Form I can advantageously be used directly as an Active Pharmaceutical Ingredient (API) to prepare formulations.
- API Active Pharmaceutical Ingredient
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprises said compound of fonnula (A) Form I and also at least one pharmaceutically acceptable excipient.
- compositions of the present compositions must be pharmaceutically acceptable.
- a "pharmaceutically acceptable" component is one that is suitable for use with humans and/or other animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.
- the compositions of the present invention are generally administered to patients, which include, but are not limited to, mammals, for example, humans, by conventional routes known in the art.
- the present invention further relates to the use of the pharmaceutical compositions of the invention for preventing and/ r treating cancer and/or tumors.
- the cancer may be chosen among sarcoma, ovarian cancer and non-small cell lung cancer.
- the tumor may be a solid tumor.
- Figure 1 is an X-ray Powder Diffractogram of crystal Form I of (2S)-2-amino-3-hydroxy-N- [2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl] phenyl]propanamide of the present invention.
- Figure 2 is Thenno-Gravimetric Analysis data of crystal Form I of (2S)-2-amino-3-hydroxy- N-[2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] propanamide of the present invention.
- Figure 3 shows water sorption/desorption isotherms recorded at 25°C of ciystal Form I of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(l Z)-2-(3,4,5-trimethoxyphenyi)ethenyl] phenyl]propanamide of the present invention.
- Example 1 Preparation of crystal Form I of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)- 2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide of formula (A) via the isolation of its hydrochloride form.
- a solution of sodium hydroxide of 1 N (55.2 ml, 55.2 mmoles) is poured into a mixture comprising isopropyl acetate (400 ml), water (150 ml) and (2S)-2- amino-3-hydroxy-N-[2-methoxy-2-[(lZ)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] propanamide hydrochloride of formula (B) (20.0 g, 45.6 mmoles) so as to reach a pH equal to 12 in the aqueous phase.
- the organic phase is collected, washed twice with 200 ml of water, and then partially concentrated. 200 ml of isopropyl acetate are then distilled at 35°C under 110 mbar. The resulting medium is cooled down to 20+5 °C and maintained at this temperature during 12 hours. The so obtained white suspension is then cooled down to 5+5°C during 1 to 2 hours before being filtered. The wet product on filter is washed twice with 20 ml of isopropyl acetate before being dried in vacuum (3.4.2 g, 77%) in order to obtain the product of formula (A). The so obtained product of formula (A) has a chemical purity higher than or equal to 99.5% as determined by High-Performance Liquid Chromatography (HPLC).
- HPLC High-Performance Liquid Chromatography
- Example 2 Preparation of crystal Form ⁇ of (2S)-2-amino-3-hydroxy-N-[2-methoxy-2-[(lZ)- 2-(3,4,5-tTiiBethoxyphenyl)ethenyl]phenyl]propanamide of formula (A) without the isolation of its hydrochloride form.
- steps (i 7 ) to ( ⁇ ') are the same as the steps (i) to (iii) as described above in scheme 1 and thus are also described in WO 2009/1 18474.
- TEA (32.0 ml, 0.230 mole) is poured into a medium comprising dichloromethane (DCM) (300 ml), compound (Z)-(Ib) (30 g, 0.085 mole) and compound of formula (IF) with Boc being the protective group (L-serine-N-BOC-acetonide ; 25.1 g, 0.102 mole) at 20°C.
- DCM dichloromethane
- Boc the protective group
- L-serine-N-BOC-acetonide 25.1 g, 0.102 mole
- T3P propanephosphonic acid anhydride
- the medium is set and maintained at reflux during about 1 hour.
- the reaction medium is then cooled down to 20-25°C and then water (300 ml) is added.
- the organic phase is washed with a solution of sodium bicarbonate at 6% (300 ml, 0.213 mole). After decantation, the organic phase is washed again with water (300 ml). After partial concentration, methanolic hydrochloride (114 ml, 0.682 mole) and methanol (114 ml) are added. The reactive medium is stirred up for about 4-5 hours at 20-25°C. Water (180 ml) is added to the medium, and then phases are decanted. The organic phase is then further extracted with water (120 ml).
- Aqueous phases are put together, and isopropyl acetate (390 ml, 13 volumes) and sodium hydroxide (69 ml, 0.690 mole) are added thereto.
- the decanted organic phase is washed twice with 240 ml of water. Charcoal is added to the organic phase and stirred at 25°C during 1 hour, and then filtered.
- the isopropyl acetate is partially distilled until 10 volumes under vacuum. The obtained slurry is cooled down to 5+5°C, maintained at this temperature during 1 hour, and then Filtered.
- the wet product on filter is washed twice with 25 ml of isopropyl acetate before being dried under vacuum at 40°C (19.2 g, 56 %) in order to obtain the product of formula (A).
- the so obtained product of formula (A) has a chemical purity higher than or equal to 99.5% as determined by HPLC.
- Said crystal Form I according to the invention was characterized by several physical methods such as X-ray Powder Diffraction, Differential Scanning Calorimetry, Thenno-Gravimetric Analysis, Water- Activity isotherm measurement, as shown below.
- Ka mean 1.54184A wavelength) running at 35 kV and 40 mA levels is used.
- a Lynx-Eye detector completes the setup. Diagrams are recorded in the following conditions: a 1.5 to 40.0° scan in angle 2 ⁇ , 10 and 100 seconds counting time per degree in 2 ⁇ , according to the amount of powder to be analyzed, and ambient conditions of pressure, temperature and relative humidity.
- the recording of a reference XRPD diagram of said Form I is carried out on a powder gently ground with agate mortar and pestle in order to reduce preferred orientation effects.
- the so obtained reference XRPD diagram for a sample of Form I is shown in Figure 1.
- the main peaks have 2-theta angles ( ⁇ 0.2 °) of 3.6, 7.1, 10.5, 11.2, 12.2 and 17.9 degrees 2-theta, more precisely of 3.6,. 7.1, 10.0, 10.5, 11.2, 12.2, 13.3, 14.3, 17.9, 18.7, 18.9 and 21.2 degrees 2-theta ( ⁇ 3 ⁇ 4 ct niean 1.54184A).
- Analyses are carried out under a nitrogen stream with a PerkinElmer Pyris Diamond analyzer.
- the calorimeter is also temperature-calibrated with indium and lead (onset temperatures of 429.8 K and 600.7 K respectively).
- Energy calibration is done with a certified indium standard (melting enthalpy of 28.7 J/g).
- a mechanical compressor (Intracooler II) is used to obtain and equilibrate the temperature program: from 290 to 465 K at a rate of 5 K/min under a constant nitrogen stream of 30 mL/min. Between 1.5 and 5 mg of the product to be analyzed is placed in a semi-open aluminum sample pan.
- said Form I according to the invention exhibits a melting point (onset) around 104°C, advantageously 104°C ⁇ 2°C.
- RH relative humidity
- Form 1 is non-hygroscopic and physically stable over the entire range of relative humidity (0% to 90% RH).
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014108066A1 (zh) * | 2013-01-11 | 2014-07-17 | 浙江大德药业集团有限公司 | 氨基康普立停衍生物的合成及其作为口服抗肿瘤药物的应用 |
EP2805705A1 (en) | 2013-05-23 | 2014-11-26 | IP Gesellschaft für Management mbH | Packaging with one or more administration units comprising a sodium salt of (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1 H-imidazol-4-yl)-propionic acid |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US5674906A (en) * | 1995-03-07 | 1997-10-07 | Ajinomoto Co., Inc. | Stilbene compounds and pharmaceutical compositions containing them |
EP1264821A1 (en) * | 2000-03-17 | 2002-12-11 | Ajinomoto Co., Inc. | Novel crystal of stilbene derivative and process for producing the same |
US20110124899A1 (en) * | 2008-02-28 | 2011-05-26 | Sanofi-Aventis | Method for preparing combretastatin |
-
2012
- 2012-12-04 WO PCT/IB2012/056953 patent/WO2013084150A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5674906A (en) * | 1995-03-07 | 1997-10-07 | Ajinomoto Co., Inc. | Stilbene compounds and pharmaceutical compositions containing them |
EP1264821A1 (en) * | 2000-03-17 | 2002-12-11 | Ajinomoto Co., Inc. | Novel crystal of stilbene derivative and process for producing the same |
US20110124899A1 (en) * | 2008-02-28 | 2011-05-26 | Sanofi-Aventis | Method for preparing combretastatin |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014108066A1 (zh) * | 2013-01-11 | 2014-07-17 | 浙江大德药业集团有限公司 | 氨基康普立停衍生物的合成及其作为口服抗肿瘤药物的应用 |
EP2805705A1 (en) | 2013-05-23 | 2014-11-26 | IP Gesellschaft für Management mbH | Packaging with one or more administration units comprising a sodium salt of (R)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1 H-imidazol-4-yl)-propionic acid |
EP3184095A1 (en) | 2013-05-23 | 2017-06-28 | IP Gesellschaft für Management mbH | Administration units comprising polymorph 1 of 2-(2-methylamino-pyrimidin-4-yl]-1h-indole-5-carboxylic acid [(s)-1-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-amide |
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